The present invention relates to a method for diagnosing vascular endothelial injury or arteriosclerotic pathology, i.e., to a method for measuring serotonin which exactly reflects the state of endothelial injury or arteriosclerosis.
Coronary artery disease has killed so many people that it is important to detect and treat it in early stages. Coronary artery disease almost always involves arteriosclerotic vascular lesions, and markers for diagnosis of arteriosclerotic pathology and its changes have been sought after. Markers which make it possible to diagnose arteriosclerosis are vital to diagnosis of arteriosclerotic diseases.
Hypercholesterolemia is a risk factor for arteriosclerosis, and cholesterol is considered as an etiogenic agent in the development of arteriosclerotic lesions. The research group organized in 1983 for studies on primary hyperlipidemia by the Ministry of Health and Welfare under a research project against specific diseases reported that the prevalence of coronary artery disease increases about five times from 2.3% to 12.9% with increase in serum cholesterol from 199 mg/dl or below to 400 mg/dl or above. In recent years, LDL cholesterol, oxidized LDL and other etiogenic agents for arteriosclerosis have been studied as diagnostic markers for diagnosis of arteriosclerotic pathology.
Another risk factor for arteriosclerotic disease under study is an inflammation marker, CRP (C-reactive protein) (Paul M. Ridker et al., The New England J. Medicine, 23, p.836, 2000) because inflammation of the arteriosclerotically injured vascular endothelium is accompanied by increase of CRP, which serves as an inflammation marker. However, because the CRP level (concentration) increases not only after vascular endothelial injury the but also after destruction of organ tissues and bacterial infection, CRP has a problem with specificity and is improper for exact diagnosis of arteriosclerotic pathology and vascular endothelial injury.
As discussed above, diagnostic markers for endothelial injury are essential important not only for diagnosis of vascular endothelial injury but also for diagnosis of arteriosclerotic pathology. The object of the present invention is to provide a substance which serves as a novel diagnostic marker for endothelial injury and arteriosclerotic pathology.
A search for a novel marker to attain the above-mentioned object hit on serotonin, the level of which in plasma increases upon development of a gastrointestinal tumor (Ming-shih Lee, et al., Clinical Chemistry, 46, p.422 (2000)) or a carcinoid tumor from secretory cells in the gastrointestinal tract (Kiyoshi Saijo, Nihon Rinsho, 53, p.527 (1995)). It is known that plasma serotonin transiently increases at the sites of stenosis in the coronary artery during coronary angioplasty (Paolo Golino et al, The New England J. Medicine, 330, P.523 (1994), and Dario Leosco et al., The American J. Cardiology, 84, p.1317 (1999)). However, it is also reported that there was no change in the plasma serotonin level in abdominal aortic blood during coronary angioplasty (Paolo Golino et al., The New England J. Medicine, 330, p.523 (1994)).
The results of measurements of serotonin in platelet-rich plasma obtained by centrifuging blood from patients with coronary artery disease for 5 minutes at 450xc3x97g revealed that the serotonin level is significantly higher in patients younger than 60 years old than in normal subjects without coronary artery disease (Kjell Vikenes et al., Circulation, 100, p.483, 1999). However, there has been no report that suggests ectoglobular free serotonin outside of the platelets in blood, or serotonin in platelet-free plasma, as a marker for diagnosis of vascular endothelial injury and arteriosclerotic pathology.
The plasma serotonin levels in carcinoid patients are higher than those in healthy people. Comparison between a group of carcinoid patients with coronary heart disease and a noncardiac group of carcinoid patients demonstrated that the plasma serotonin level in the cardiac group was significantly higher (Paul A. et al., Circulation, 92, p.790-795 (1995)). However, the results were obtained with a particular group of patients having carcinoids with high plasma serotonin levels and do not suggest association of plasma serotonin with vascular endothelial injury or arteiosclerotic disease in non-carcinoid individuals.
Therefore, in order to attain the above-mentioned object, according to the first aspect of the present invention, the present invention provides a method for diagnosing vascular endothelial injury, which comprises measuring the serotonin level in a plasma sample. In order to attain the above-mentioned object, according to the second aspect of the present invention, the present invention provides a method for diagnosing vascular endothelial injury, which comprises measuring the ratio of the serotonin level in a plasma sample to the serotonin level in a blood sample, a serum sample or a platelet sample. In order to attain the above-mentioned object, according to the third aspect of the present invention, the present invention provides a method for diagnosing arteriosclerotic pathology, which comprises measuring the serotonin level in a plasma sample. In order to attain the above-mentioned object, according to the fourth aspect of the present invention, the present invention provides a method for diagnosing arteriosclerotic pathology, which comprises measuring the ratio of the serotonin level in a plasma sample to the serotonin level in a blood sample, a serum sample or a platelet sample. Now, the present invention is described in detail.